Despite considerable advances in the treatment of cardiovascular disease (CVD), it remains one of the leading causes of death in developed countries. Several large-scale prospective epidemiological studies provided overwhelming evidence that low plasma levels of high-density lipoprotein cholesterol (HDL-C) is a major, independent risk factor for CVD. Studies in genetically modified animal models and in subjects with rare disorder of HDL metabolism support a causal relationship between low HDL and development of atherosclerotic vascular disease. It is noteworthy that a low level of HDL-C (generally regarded by current treatment guidelines as <40 mg/dL or <1.0 mmol/L in men and <50 mg/dL or <1.3 mmol/L in women) remains predictive of future cardiovascular risk, even when the concentration of cholesterol in LDL has reached low levels by treatment with statins (Barter P, Gotto A M, LaRosa J C, et al. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N Engl J Med. Sep. 27 2007; 357(13): 1301-1310).
While this atheroprotective activity of HDL is now widely accepted, the mechanism that supports this effect is still debated. The most well-established mechanism by which HDLs protect against atherosclerosis is by promoting cholesterol efflux from macrophages and transporting the cholesterol to the liver for excretion in bile and faeces, a process called ‘reverse’ cholesterol transport’ (RCT). In addition, this ateroprotective role of HDLs may also be related to their anti-oxidative, anti-inflammatory, anti-apoptotic, or endothelial protective properties, so called pleiotropic effects (Calabresi L, Gomaraschi M, Franceschini G. Endothelial protection by high-density lipoproteins: from bench to bedside. Arterioscler Thromb Vase Biol. Oct. 1 2003; 23(10):1724-1731; von Eckardstein A, Hersberger M, Rohrer L. Current understanding of the metabolism and biological actions of HDL. Curr Opin Clin Nutr Metab Care. March 2005; 8(2): 147-152). These protective pleiotropic effects of HDL lead to the concept that therapies to enhance plasma HDL-C levels would be anti-atherogenic and protective against cardiovascular events. However, HDLs are highly heterogeneous with subclasses that differ in density, size, charge and protein composition, which have different functions and may differ in their functional anti-atherogenic properties. Furthermore, several environmental factors, like cigarette smoking, alcohol consumption and physical activity or inflammatory condition are known to influence plasma HDL-C levels. Given the complexity of the HDL system, it has emerged that single measurement of HDL-C levels often fails to provide a reliable prediction of HDL's biological activities in protecting against CVD and thus is frequently a poor indicator of protection or risk at the individual subject level. Therefore, new biological markers reflecting vascular or metabolic activities of HDL particles are needed to better evaluate subject status regarding cardiovascular risk or to evaluate the responsiveness of subjects to the emergent HDL-related therapies.